The long-term objective of our research is to discover the molecular mechanisms involved in the development of the cardiovascular system. We use the human genetic approach as the window into the genetic processes involved in the development of the heart and blood vessels. We are currently using this approach to identify the first gene for Klippel-Trenaunay syndrome (KTS), which is a vascular disease comprised of capillary, lymphatic, and venous malformations associated with bony and soft tissue hypertrophy. Because KTS is a vascular anomaly, we propose that KTS pathogenesis involves the disruption of the key genes for vascular morphogenesis during embryonic development. We have characterized a KTS translocation involving chromosomes 5 and 11, and identified a novel vascular gene, VEG5Q (Vascular Endothelial Gene on 5q), as the strong candidate gene for KTS. The goals of this proposal are to use these unique resources to functionally characterize the VEG5Q gene, to investigate its normal function involved in vascular morphogenesis, and to elucidate the pathogenic mechanisms of KTS-associated mutations. The specific aims are: 1) Molecular characterization of VEG5Q, a novel vascular gene and a strong candidate for KTS. 2) To generate mouse models that will elucidate the role of VEG5Q in vascular morphogenesis. 3) To identify proteins that interact with VEG5Q. 4) Genotype-phenotype correlation studies of KTS patients and identification/characterization of genes associated with 11p translocation breakpoint. 5) Identification of genes which are differentially expressed in KTS patients using the Gene-Chip technology. The successful accomplishment of goals in this study should allow us to understand the molecular mechanisms underlying KTS as well as other common vascular disorders such as varicose veins and venous malformations. The availability of KTS genes provides the groundwork and offers the exciting possibility of characterizing the molecular mechanisms underlying vascular morphogenesis. Moreover, understanding the genetic mechanisms underlying KTS offers possibilities for treatment of KTS as well as conditions such as cancer that depend on angiogenesis.